PT86998B - 9-ETHYL-6,9-DIHYDRO-4,6-DIOXO-10-PROPYL-4H-PYRENE (3,2-G) QUINOLINE-2, 3-CARBOXYLIC ACID INGREDIENT FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION CONTAINING AN ACTIVE INGREDIENT 8-DICARBOXYLIC ACID - Google Patents

Abstract

A pharmaceutical composition comprising, as active ingredient, 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-­pyrano(3,2-g)quinoline-2,8-dicarboxylic acid or a pharmaceutically acceptable derivative thereof in admixture with a pharmaceutical acceptable adjuvant or excipient, the composition being suitable for topical administration to a patient's skin but not suitable for administration orally or to the patient's eye.

Also described is the use of 9-ethyl-6,9-dihydro-­4,6-dioxo-10-propyl-4H-pyrano(3,2-g)quinoline-2,8-­dicarboxylic acid or a pharmaceutically acceptable derivative thereof as active ingredient in the manufacture of a medicament for the treatment of various dermatological disorders.

Description

DESCRIPTIVE MEMORY

The present invention relates to the process for the preparation of pharmaceutical compositions containing 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyran- (3, 2-g) quinoline-2,8-dicarboxylic acid and methods of treatment using them.

United Kingdom Patent Number 2022078 describes several pyranquinolines prescribed for use in the treatment of, inter alia, regressive airway obstruction. The description of these compounds indicates that they are administrable through the esophagus or by inhalation. United Kingdom Patent 2157291 describes a pressurized aerosol formulation of one of these pyroquinolines, known as nedocromil sodium, which consists of the 9-ethyl-6,9-dihydro acid sodium salt -4.6). ; -dioxo-10-propyl-4H-pyran (3,3-g) quinoline-2,8-dicarboxylic,

- also indicated for the treatment of regressive airway obstruction.

In general, the pyran-quinoline compounds described in the previous references are made up of highly polar hydrophilic molecules. Therefore, they are not expected to be absorbed through the skin with sufficient intensity to provide therapeutic levels of the compounds in the subepithelial tissues.

However, it was surprisingly found that compositions containing 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyran (3,2-g) quinoline as an active ingredient -2,8-dicarboxylic or a pharmaceutically acceptable derivative thereof, are effective for the treatment of various dermatological diseases, when applied topically to the skin.

According to the present invention there is provided a pharmaceutical composition which incorporates 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyran (3,2-g) as an active ingredient ) quinoline-2,8-dicarboxylic or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant or excipient, the composition being suitable for topical administration to the skin in a patient, but not suitable. for oral administration or over the patient's eyes.

Pharmaceutically acceptable derivatives of the active ingredient include pharmaceutically acceptable metal ion salts, such as alkali metal salts, for example, di-sodium and di-potassium salts, and alkaline earth metal salts, for example calcium and magnesium salts. Gon is considered especially preferred the di-sodium salt, which is commonly known as nedocromil sodium.

The composition can contain between 0.5 and 20% w / w, preferably between 1.0 and 10% w / w, for example 4% w / w, of active ingredient.

It is preferable that the composition is a cream. The cre • me can be of the water-in-oil type, or more preferably of

like oil-in-water.

The cream preferably incorporates one or more emulsifying agents. Emulsifying agents suitable for oil-in-water creams include sodium, potassium, ammonium and triethanol-amine soaps; poly sorbates; and cationic, anionic and non-ionic emulsifying waxes. For water-in-oil creams, suitable emulsifying agents include calcium soaps, lanolin, lanolin alcohols, beeswax and various sorbitan esters.

The cream generally contains an effective proportion of an acceptable preservative or sterilizing agent suitable for a cream. Examples of preservatives that can be used are chlorobutol, chlorocresol, methyl p-hydroxy-benzoate (either alone or in combination with propyl p-hydroxy-benzoate) and thiomersal, a preservative can be present up to a level with between 0.05 and 1.0% w / w, more preferably between 0.1 and 0.5%, for example 0.2%.

cream can be buffered to pH values between 3.0 and 7.0, preferably to pH values of 4.0 and 6.5 and most preferably to pH values between 5.0 and 6.0.

Thus, in accordance with a preferred aspect of the present invention, an oil-in-water buffered pharmaceutical cream is provided for pH values between 3.0 and 7.0 and incorporating as active ingredient 9-ethyl- 6,9-dihydro-4,6-dioxo-10-propyl-4H-pyran (3,2-g) sodium quinoline-2,8-dicarboxylate.

The oily phase of the oil-in-water type cream is preferably constituted by liquid paraffin. The oil phase preferably incorporates one or more emulsifying agents, for example long chain alcohol, such as for example cetostearyl alcohol, or a fatty acid ester, such as self-emulsifying glyceryl monostearate. The oily phase

- 3 X

it can also incorporate one or more emollients, for example isopropyl myristate and one or more additional surfactants, for example one or more ketomacrogol ethers. preference to me.

The oil phase consists of between 20 and 40% w / w of the aqueous crephase, it may incorporate a buffering agent, because of a weak acid. Suitable acids include

For example, salt is carboxylic acids, for example acetic acid and particularly citric acid.

Suitable salts include alkali metal salts, for example sodium or potassium.

The aqueous phase can also incorporate one or more baotericidal and / or fungicidal preservatives, for example potassium sorbate and methyl hydroxy-benzoate.

The composition according to the present invention can also be formulated as an ointment, a lotion or liniment, or as a powder for sprinkling.

In ointments, the active ingredient is preferably finely divided and dispersed in a wax, fat, protein or paraffinic base, preferably a soft paraffin base if liquid paraffin, paraffin oil and lanolin can be incorporated into the ointment.

Na ba

It is preferable to use ointments that contain a major proportion (for example 70-90 $ w / w) of a soft white or yellow paraffin and optionally containing smaller proportions of a liquid paraffin (5-15 $ w / w) and a paraffin hard (0-12 $ w / w).

The ointment may also contain other liquid components, for example water or polyethylene glycol to improve the consistency of the base, to provide an active ingredient so that the ingredient is filtrated and / or to change the active ingredient's flavor from the solvent to , the inactive can be this libase rate.

Lotions and liniments preferably incorporate

a solution or dispersion of the active ingredient in an aqueous or oily base. A suitable preservative can be incorporated into the formulation. When pastes, gels, or emulsions are desired, a thickening agent can be incorporated into the aqueous base. Suitable thickening agents include crosslinked polymers, soluble cellulose derivatives and polyvinyl alcohol.

Sprinkling powders may contain two or more ingredients mixed together in the form of fine powder. Alternatively, the active ingredient can be applied as a solution or suspension in a liquid vehicle, to the surface of a solid vehicle and then the coated particles are dried. Examples of solid vehicles, which are normally sterilized, are co, starch, lactose, zinc oxide, light kaolin and calcium carbonate.

When solid particles of the active ingredient are present, for example in a dispersion or suspension or in a powder formulation, it is preferable that they have an average particle size between 0.01 and 10 microns.

The compositions according to the present invention po. They can be prepared by mixing the ingredients, for example by mixing or dry grinding the solid ingredients together, or by emulsifying an aqueous solution of the active ingredient with an appropriate oily base. The final pH of the solution can be controlled by adding an appropriate amount acid or base.

Creams can be prepared by dissolving the active ingredient in water buffered to the desired pH and adding the solution to the ingredients of the molten oil phase, in a homogenizer at a temperature between 40 and 90 ° C. After homogenization and cooling, if suitable containers, for example tubes, with the cream.

Preferably, the composition is administered on the skin of a patient by simply rubbing or spreading the cream on the skin that is affected or that may be affected.

The frequency of application of the composition will depend on the severity of the disease to be treated and the area of the skin over which it is observable. Repeated applications can be made at regular intervals throughout the day, for example 1 to 6 times daily, preferably twice a day. The composition can be applied prophylactically, but it is most commonly applied to an area that is already affected.

The composition is used for the treatment of various diseases in mammals, especially in humans, cats, dogs and horses, when conditions are observed that imply mastoid skin cells and / or delayed hypersensitivity reactions (cellular) and / or when observed inflammation.

The composition is of particular interest for the treatment of atopic eczema in men.

The other specific states in man and animals that can be treated, include sensitivity to contact, for example to chromium, nickel or an antibiotic; rashes caused by drugs; psoriasis; dermatitis; aphthous ulcers; Behcet's syndrome; pemphigus; urticaria; pigmented urticaria; Crohn's disease ulcers; gangrenous pyoderma; chronic skin ulcers; burns; bee or wasp stings; herpetic infections; and dermatological diseases such as systemic sclerosis (also known as systemic scleroderma), morphea (also known as circumscribed or localized scleroderma) and modular dermal fibrosis (also known as tofibroma derma) that involves excessive fibrosis.

Thus, according to a further aspect of the present invention, the use of 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyran (3,2- g) quinoline-2,8-dicarboxylic acid or a pharmaceutically acceptable salt thereof as active ingredients for the preparation of a medicine, for the treatment of a dermatological disease chosen from the group consisting of atopic eczema, sensitivity to contact, rashes caused by drugs , psoriasis, dermatitis, effective ulcers, Behcet's syndrome, pemphigus, urticaria, pigmented urticaria, Crohn's disease ulcers, pyoderma gangrene-

sa, chronic skin ulcers, burns, bee and wasp stings, herpetic infections, and dermatological diseases that involve excessive fibrosis, by topical administration on the skin of a patient suffering from such disease.

The amount of active ingredient that is administered will, of course, depend on the condition to be treated, the animal and the patient to be treated, the particular derivative used and the mode of administration. However, it is possible to achieve generally satisfactory results when the active agent is administered in a dosage comprised between 1 and 100, and preferably between 10 and 75 mg per kg of body weight of the animal. For men, the daily dosage prescribed is comprised between 1 mg and 3,500 mg, preferably between 1 mg and 1,500 mg and more preferably between 1 mg and 600 mg, which can be administered in divided doses 1 to 6 times per day. As is usual when treating a skin condition topically, for example using a cream, it is difficult to control the dosage, but this will generally depend on the size and condition of the area to be treated.

The invention is illustrated but not limited, with the following examples. Example 1. Oil-in-water cream Ingredients Oily phase BP glyceryl monostearate 4.0 BP ceto-stearyl alcohol 4.0 BP liquid paraffin 10.0 BP isopropyl myristate 5.0 Cremofor A6 * 2.0 Cremofor A25 * 2.0 Propyl hydroxy-benzoate BP 0.1

Aqueous Phase

Methyl hydroxy-benzoate BP0.1

Potassium sorbate BP0.2

BP pure water (low metallic content) 67.22

BP1.3 sodium acid citrate

BP0.08 sodium hydroxide

Active Ingredients4.0

9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyran (3,2-g) quinoline-2,8-dicarboxylate

I sodium m Cremofor Aó and Cremofor A25 are trademarks.

I Method

The components of the oil phase are placed in a mixing vessel and fused with stirring at 60-70 ° C.

The active ingredient is added to the buffered aqueous phase, dissolved under gentle heating and then the hot aqueous layer is added to the aqueous phase with vigorous stirring. After the addition and homogenization is complete, the mixture is allowed to cool under gentle agitation and then 20 ml tubes are filled with it at room temperature.

I Example 2: Oil-in-water cream

Ingredients

Oily Phase

JLeZ

Glyceryl mono-stearate BP4.0

BP4.0 ceto-stearyl alcohol

BP15.0 liquid paraffin

Cremofor Aóm2,0

Cremofor A25 * 2.0

Propyl hydroxy-benzoate BP0.1

Aqueous Phase % P / P BP methyl hydroxy benzoate 0.1 BP potassium sorbate 0.2 BP pure water (low metallic content) 67.22 BP sodium acid citrate 1.3 BP sodium hydroxide 0.08 Active Ingredient: 4.0

9-ethyl-6,9-dihydro-4, o-dioxo-19-propyl-4H-pyran (3,2-g) sodium quinoline-2,8-dicarboxylate m Cremofor Aó and Cremofor A25 are trademarks .

Method

This composition was prepared by the method of Example 1 and had improved conservation characteristics.

Example 3: Ointment

JLpZk Ingredients

BP10 Liquid Paraffin

Lanolin BP10

BP70 soft white paraffin

Active ingredient: 10

Sodium 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyran (3,2-g) quinoline-2,8-dicarboxylate.

Method

It was prepared by dispersing the finely divided active ingredient in a molten mixture of the other components, in a mixing vessel at a temperature of 60-70 ° C. After homogenization, the mixture was allowed to cool, and tubes of 20 ml were filled with it. ml at room temperature.

Example 4 * Oily Lotion Ingredients $ w / w arachidic oil 85

Active ingredient: 15

Sodium 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyran (3,2-g) quinoline-2,8-dicarboxylate

Method

It was prepared by dispersing the finely divided active ingredient in oil.

Example 5: Shovel for sprinkling

Ingredients% w / p zinc oxide25

Purified talc 10

Sterilizable corn starch55

Active Ingredient: 10 | 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyran (3,2-g) quinoline-2,8 ~ sodium dicarboxylate

Method

He prepared himself by grinding the various ingredients together.

Example 6: Skin Permeability Measures

In the following tests, the penetration of the active ingredient through human skin and shaved rat skin was demonstrated for several formulations:

Rapa rats were sacrificed for cervical dislocation | for both sexes aged 8 to 12 weeks, the dorsal skin was excised and subcutaneous fat was removed with minimal handling. Human epidermis members were prepared by immersing the complete skin (epidermis plus dermis) in water at 60 ° C for 30 seconds, removing and gently giving the epidermis through thick needles. Care has been taken to ensure minimal handling of the skin membrane. Then the assembly was done with the epidermis side facing upwards under a horizontal diffusion glass cell, a donor chamber was fixed in position and fastened with a clamp. The reception medium was constituted by aqueous ethanol a (v / v) and the cells were mounted in a water bath at 37 ° C thermostatically controlled.

The formulation intended to be tested was applied uniformly on the epidermis side of the sample. After one

predetermined time, the reception medium was removed, filtered and analyzed for determination of the active ingredient, by high pressure liquid chromatography (HPLC).

Claims (1)

Process for the preparation of a pharmaceutical composition characterized by incorporating, as an active ingredient, 0.5 to 20% w / w, preferably 1.0 to 10% w / w or a pharmaceutically acceptable derivative thereof in addition to a pharmaceutically acceptable adjuvant or excipient in a form suitable for topical administration to the patient's skin but not suitable for oral administration or to the patient's eyes. - 2nd - Process according to claim 1, characterized in that the active ingredient is in the form of a pharmaceutically acceptable metal ion salt. - 3rd - Process according to claim 2, characterized in that the active ingredient is 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyran (3,2-g) quinoline-2 , Di-sodium 8-dicarboxylate. - 4th - Process according to any one of the preceding claims, characterized in that the composition is a cream. - Process according to claim 4, characterized in that the cream is an oil in water cream. Process according to claim 4 or. 5, characterized in that the cream has a pH between 3.0 and 7.0. 7. The process of claim 6, characterized in that the pH is between 5.0 and 6.0. - 8th - Process according to any one of claims 4 to 7, characterized in that the active ingredient is dissolved in buffered water at the desired pH and the solution is added to the ingredients of the melted oil phase at a temperature between 40 and 90 ° C approximately. - ga - Process according to any of claims 1 to 3, characterized in that the composition is in the form of a liniment or lotion, - 10ê - Process according to any of claims 1 to 3, characterized in that the composition is in the form of a powder. The applicant declares that the first applications for this patent were filed in Great Britain on 17 March 1987 and on 14 January 1988, under Nos. 87/06242 and 88/00833, respectively ·